Design of a Library of Potential Inhibitors to Farnesyltransferase
Haas, Eric J.
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Insight Pancreatic cancer is the fourth most common cause of cancerrelated deaths. Patients have a survival rate of less than 5% within a five-year span. On average, patients die about two and a half years post-diagnosis after the cancer spreads. Why? Pancreatic cancer is difficult to detect during its early stages because its symptoms are not obvious. As a result, pancreatic cancer is typically in its advanced form once diagnosed. At this point, the cancer is difficult to eliminate because the tumors may have spread to other tissues, or metastasized. What is the pancreas? The pancreas is a vital digestive gland that aids in digestion of food by secreting digestive enzymes that combine with pancreatic juice to break down protein, fats, and sugars. Aside from secreting enzymes, the pancreas also secretes hormones such as insulin and glucagon to regulate glucose levels. Target Generally, healthy cells grow and divide with the help of a signal transmitted by the Ras protein. Ras is a “G-protein” because guanine nucleotides (GTP and GDP) are bound to them. Ras is turned on by replacing GDP with GTP. When Ras protein is activated, it signals the cells to grow by MAP Kinase cascade. When the gamma phosphate is hydrolyzed off the GTP and converted back to GDP, Ras is turned off and cell growth is signaled to stop. Mutations in Ras cause its signal to be constitutively, or continuously, expressed and lead to uncontrolled signaling for cell growth. Ras depends on post-translational modification by the zincmetalloenzyme farnesyltransferase (FTase). After translation, Ras goes through four modification steps; the first step includes FTase. The farnesyl group is necessary for Ras to attach to the cell membrane. If Ras does not attach to the cell membrane, then Ras cannot transfer signals from receptors and signal the cell to grow. If the post translational modification of farnesyltransferase is inhibited by small molecule inhibitors, mutant Ras is mislocalized. When the constitutively active Ras is mislocalized the MAP Kinase cascade is disrupted and the uncontrolled cell growth is halted.